During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.

Time for primary review: 38 days Aims Hazardous environmental and genetic factors can damage endothelial cells to induce atherosclerotic vascular disease. Recent studies suggest that class III deacetylase SIRT1 may promote cell survival via novel antioxidative mechanisms. The current study tested the hypothesis that SIRT1, specifically overexpressed in the endothelium, is atheroprotective. Methods and results Human umbilical vein endothelial cells (HUVECs) were used to study the effects of oxidized low-density lipoprotein (LDL) on SIRT1 expression. Endothelial cell-specific SIRT1 transgenic (SIRT1-Tg) mice were used to study the effects of SIRT1 on aortic vascular tone. SIRT1-Tg mice were crossed with apolipoprotein E null (apoE 2/2 ) mice to obtain SIRT1-Tg/apoE 2/2 mice for the analysis of atherogenesis in the presence of endothelial overexpression of SIRT1. SIRT1 expression in HUVECs was increased by the treatment with oxidative LDL. Adenoviral-mediated overexpression of SIRT1 was protective of apoptosis of HUVECs. Calorie restriction increased, whereas high-fat diet decreased, the SIRT1 expression in mouse aortas. In SIRT1-Tg mice, high fat-induced impairment in endotheliumdependent vasorelaxation was improved compared with that of wild-type littermates. This was accompanied by an upregualtion of aortic endothelial nitric oxide synthase expression in the SIRT1-Tg mice. The SIRT1-Tg/apoE 2/2 mice had less atherosclerotic lesions compared with apoE 2/2 controls, without affecting blood lipids and glucose levels. Conclusion These results suggest that endothelium-specific SIRT1 overexpression likely suppresses atherogenesis via improving endothelial cell survival and function.

Besides genome editing, CRISPR-Cas12a has recently been used for DNA detection applications with attomolar sensitivity but, to our knowledge, it has not been used for the detection of small molecules. Bacterial allosteric transcription factors (aTFs) have evolved to sense and respond sensitively to a variety of small molecules to benefit bacterial survival. By combining the single-stranded DNA cleavage ability of CRISPR-Cas12a and the competitive binding activities of aTFs for small molecules and double-stranded DNA, here we develop a simple, supersensitive, fast and high-throughput platform for the detection of small molecules, designated CaT-SMelor ( C RISPR-Cas12a- and aT F-mediated s mall m ol e cu l e detect or ). CaT-SMelor is successfully evaluated by detecting nanomolar levels of various small molecules, including uric acid and p -hydroxybenzoic acid among their structurally similar analogues. We also demonstrate that our CaT-SMelor directly measured the uric acid concentration in clinical human blood samples, indicating a great potential of CaT-SMelor in the detection of small molecules.

The solution behavior of the largest inorganic acid known thus far, the neutral, spherical iron/molybdenum/oxide nanocluster {Mo72Fe30} ([triple bond{(MoVI) MoVI5}12FeIII30 1a), including the pH-controlled deprotonation, is reported. The acidic properties are due to the 30 peripheral, weakly acidic FeIII(H2O) groups that form a unique Archimedean solid with all edges and dihedral angles being equal, the icosidodecahedron, and therefore an "isotropic" surface. Interestingly, the aqueous solutions are stable even for months because of the inertness of the spherical solutes and the presence of the hard FeIII and MoVI centers. The stability can be nicely proven by the very characteristic Raman spectrum showing, because of the (approximately) icosahedral symmetry, only a few lines. Whereas the {Mo72Fe30} clusters exist as discrete, almost neutral, molecules in aqueous solution at pH< 2.9, they get deprotonated and self-associate into single-layer blackberry-type structures at higher pH while the assembly process (i.e., the size of the final species) can be controlled by the pH values; this allows the deliberate generation of differently sized nanoparticles, a long-term goal in nanoscience. The average hydrodynamic radius (Rh) of the self-assembled structures decreases monotonically with increasing number of charges on the {Mo72Fe30} macroanions (from approximately 45 nm at pH approximately 3.0 to approximately 15 nm at pH approximately 6.6), as studied by laser light scattering and TEM techniques. The {Mo72Fe30} macroions with high-stability tunable charges/surfaces, equal shape, and masses provide models for the understanding of more complex polyelectrolyte solutions while the controllable association and dissociation reported here of the assembled soft magnetic materials with tuneable sizes could be interesting for practical applications.